The benefit of autologous transplantation in newly diagnosed multiple myeloma has been confirmed by follow-up of the IFM 2009 trial, reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition by Aurore Perrot, MD, PhD, Assistant Professor of Hematology at the Cancer University Institute Oncopole, Toulouse, France.1
“After 8 years of follow-up, the results confirm that high-dose melphalan and transplant is associated with a 30% reduced risk of disease progression or death,” Dr. Perrot said. “We saw that 35% of patients in the transplant group did not relapse, and this was without excess toxicity, including second malignancies.”
Aurore Perrot, MD, PhD
Suzanne Lentzsch, MD, PhD
Suzanne Lentzsch, MD, PhD, Professor of Medicine and Director of the Multiple Myeloma and Amyloidosis Service at Columbia University, New York, considered IFM 2009 “one of the most important presentations at ASH,” noting that the study “finally provides critical data to physicians and newly diagnosed patients who struggle to decide whether they should opt for an immediate transplant or only collect stem cells for a delayed transplant.”
IFM 2009 Shows ASCT Benefits
In IFM 2009, 700 newly diagnosed patients were randomly assigned to the combination of eight cycles of lenalidomide, bortezomib, and dexamethasone (RVd) or three cycles of RVd plus high-dose melphalan with autologous stem cell transplantation (ASCT) followed by two consolidation RVd cycles. All patients received lenalidomide maintenance for 12 months.
“More than 60% of patients are alive in the two arms at 8 years’ follow-up. Front-line transplant remains our first choice, with a view to cure patients,” said Dr. Perrot.
In the second interim analysis, performed in June 2015 after 44 months’ follow-up, the median progression-free survival, the primary endpoint, was 50 months in the transplant arm and 36 months with RVd alone (P < .001).2
In the current analysis, after a median follow-up of 89.8 months, median progression-free survival was 47.2 months after ASCT and 35 months with RVd (hazard ratio [HR] = 0.70; 95% confidence interval [CI] = 0.59–0.83). All subgroups benefited from transplant, including patients with high-risk cytogenetics.
“Transplant was superior to RVd alone, even in patients who achieved undetectable disease, ie, minimal residual disease [MRD] at 106,” Dr. Perrot reported. The MRD negativity rate was 29.8% with transplant and 20% with RVd (P = .01).
“After 8 years of follow-up, the results confirm that high-dose melphalan and transplant is associated with a 30% reduced risk of progression or death.”— Aurore Perrot, MD, PhD
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Second-Line Therapy Was Effective
Relapses occurred in 270 patients in the RVd arm and 227 in the transplant arm; second-line therapy (by physician’s choice) was received by 262 and 217, respectively. For approximately 100 patients in each arm, this second-line option was pomalidomide; use of carfilzomib and daratumumab was limited in this study. In the RVd arm, 201 patients received a late transplant; in the transplant arm, 49 received another transplant.
“Of note, 23% of patients who relapsed after RVd and needed a second-line regimen did not get a transplant,” she noted. “On the other arm, 38% of the original transplant group did not need a second-line regimen.”
Second progression-free survival was defined as the time from randomization to disease progression on the next line of therapy or death from any cause. Median second progression-free survival was not reached in the transplant arm and was 95.3 months in the RVd arm (HR = 0.96; 95% CI = 0.76–1.21).
“Thanks to the efficacy of salvage therapy, [second progression-free survival] was similar between the arms,” she said. “Overall survival was similar, too. Interestingly, more than 60% of patients in both arms were alive after 8 years of follow-up.”
“[IFM 2009] finally provides critical data to physicians and newly diagnosed patients who struggle to decide whether they should opt for an immediate transplant or only collect stem cells for a delayed transplant.”— Suzanne Lentzsch, MD, PhD
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No Meaningful Differences in Tolerability
“Of course, there was more hematologic toxicity after infusion of high-dose melphalan in the transplant group, but otherwise there were no differences in global health-related quality of life, physical functioning, and role functioning scores,” Dr. Perrot reported.
After 8 years, there was also no difference in second primary malignancies, which occurred in 7.7% of the RVd arm and 9.7% of the transplant arm. Myelodysplastic syndromes or acute myeloid leukemia was seen in less than 2% per arm.
Dr. Perrot predicted that post-ASCT outcomes may be even further improved by adding daratumumab to RVd. This strategy is based on data from the phase III CASSIOPEIA trial, in which bortezomib, thalidomide, dexamethasone, plus daratumumab, given with ASCT, improved the depth of response and progression-free survival.3
“We assume that the combination of transplant with the most efficient quadruplet is the best approach to curing as many patients as possible,” she said.
DISCLOSURE: Dr. Perrot has served as a consultant for or received honoraria from Amgen, BMS/Celgene, Janssen, Sanofi, and Takeda. Dr. Lentzsch has served as a consultant for or received honoraria from Sorrento, Janssen, Celularity, GSK, Takeda, AbbVie, Sanofi, and Karyopharm and has an equity ownership or served on the board of directors for Caelum Biosciences.
REFERENCES
1. Perrot A, Lauwers-Cances V, Cazaubiel T, et al: Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: Long-term follow-up analysis of the IFM 2009 trial. 2020 ASH Annual Meeting & Exposition. Abstract 143. Presented December 5, 2020.
2. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.
3. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomized, open-label, phase 3 study. Lancet 394:29-38, 2019.
